0:00:00.000,0:00:03.000
What I want to talk to you about

0:00:03.000,0:00:05.000
is what we can learn from studying the genomes

0:00:05.000,0:00:07.000
of living people

0:00:07.000,0:00:09.000
and extinct humans.

0:00:09.000,0:00:11.000
But before doing that,

0:00:11.000,0:00:14.000
I just briefly want to remind you about what you already know:

0:00:14.000,0:00:16.000
that our genomes, our genetic material,

0:00:16.000,0:00:19.000
are stored in almost all cells in our bodies in chromosomes

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in the form of DNA,

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which is this famous double-helical molecule.

0:00:24.000,0:00:26.000
And the genetic information

0:00:26.000,0:00:28.000
is contained in the form of a sequence

0:00:28.000,0:00:30.000
of four bases

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abbreviated with the letters A, T, C and G.

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And the information is there twice --

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one on each strand --

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which is important,

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because when new cells are formed, these strands come apart,

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new strands are synthesized with the old ones as templates

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in an almost perfect process.

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But nothing, of course, in nature

0:00:49.000,0:00:51.000
is totally perfect,

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so sometimes an error is made

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and a wrong letter is built in.

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And we can then see the result

0:00:58.000,0:01:00.000
of such mutations

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when we compare DNA sequences

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among us here in the room, for example.

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If we compare my genome to the genome of you,

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approximately every 1,200, 1,300 letters

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will differ between us.

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And these mutations accumulate

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approximately as a function of time.

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So if we add in a chimpanzee here, we will see more differences.

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Approximately one letter in a hundred

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will differ from a chimpanzee.

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And if you're then interested in the history

0:01:29.000,0:01:31.000
of a piece of DNA, or the whole genome,

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you can reconstruct the history of the DNA

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with those differences you observe.

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And generally we depict our ideas about this history

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in the form of trees like this.

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In this case, it's very simple.

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The two human DNA sequences

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go back to a common ancestor quite recently.

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Farther back is there one shared with chimpanzees.

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And because these mutations

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happen approximately as a function of time,

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you can transform these differences

0:02:00.000,0:02:02.000
to estimates of time,

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where the two humans, typically,

0:02:04.000,0:02:08.000
will share a common ancestor about half a million years ago,

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and with the chimpanzees,

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it will be in the order of five million years ago.

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So what has now happened in the last few years

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is that there are account technologies around

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that allow you to see many, many pieces of DNA very quickly.

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So we can now, in a matter of hours,

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determine a whole human genome.

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Each of us, of course, contains two human genomes --

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one from our mothers and one from our fathers.

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And they are around three billion such letters long.

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And we will find that the two genomes in me,

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or one genome of mine we want to use,

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will have about three million differences

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in the order of that.

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And what you can then also begin to do

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is to say, "How are these genetic differences

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distributed across the world?"

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And if you do that,

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you find a certain amount of genetic variation in Africa.

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And if you look outside Africa,

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you actually find less genetic variation.

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This is surprising, of course,

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because in the order of six to eight times fewer people

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live in Africa than outside Africa.

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Yet the people inside Africa

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have more genetic variation.

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Moreover, almost all these genetic variants

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we see outside Africa

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have closely related DNA sequences

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that you find inside Africa.

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But if you look in Africa,

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there is a component of the genetic variation

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that has no close relatives outside.

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So a model to explain this

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is that a part of the African variation, but not all of it,

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[has] gone out and colonized the rest of the world.

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And together with the methods to date these genetic differences,

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this has led to the insight

0:03:49.000,0:03:51.000
that modern humans --

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humans that are essentially indistinguishable from you and me --

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evolved in Africa, quite recently,

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between 100 and 200,000 years ago.

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And later, between 100 and 50,000 years ago or so,

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went out of Africa

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to colonize the rest of the world.

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So what I often like to say

0:04:11.000,0:04:13.000
is that, from a genomic perspective,

0:04:13.000,0:04:15.000
we are all Africans.

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We either live inside Africa today,

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or in quite recent exile.

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Another consequence

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of this recent origin of modern humans

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is that genetic variants

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are generally distributed widely in the world,

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in many places,

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and they tend to vary as gradients,

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from a bird's-eye perspective at least.

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And since there are many genetic variants,

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and they have different such gradients,

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this means that if we determine a DNA sequence --

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a genome from one individual --

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we can quite accurately estimate

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where that person comes from,

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provided that its parents or grandparents

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haven't moved around too much.

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But does this then mean,

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as many people tend to think,

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that there are huge genetic differences between groups of people --

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on different continents, for example?

0:05:07.000,0:05:10.000
Well we can begin to ask those questions also.

0:05:10.000,0:05:13.000
There is, for example, a project that's underway

0:05:13.000,0:05:15.000
to sequence a thousand individuals --

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their genomes -- from different parts of the world.

0:05:18.000,0:05:21.000
They've sequenced 185 Africans

0:05:21.000,0:05:24.000
from two populations in Africa.

0:05:24.000,0:05:27.000
[They've] sequenced approximately equally [as] many people

0:05:27.000,0:05:30.000
in Europe and in China.

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And we can begin to say how much variance do we find,

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how many letters that vary

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in at least one of those individual sequences.

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And it's a lot: 38 million variable positions.

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But we can then ask: Are there any absolute differences

0:05:46.000,0:05:48.000
between Africans and non-Africans?

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Perhaps the biggest difference

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most of us would imagine existed.

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And with absolute difference --

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and I mean a difference

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where people inside Africa at a certain position,

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where all individuals -- 100 percent -- have one letter,

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and everybody outside Africa has another letter.

0:06:06.000,0:06:09.000
And the answer to that, among those millions of differences,

0:06:09.000,0:06:12.000
is that there is not a single such position.

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This may be surprising.

0:06:16.000,0:06:19.000
Maybe a single individual is misclassified or so.

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So we can relax the criterion a bit

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and say: How many positions do we find

0:06:23.000,0:06:25.000
where 95 percent of people in Africa have

0:06:25.000,0:06:27.000
one variant,

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95 percent another variant,

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and the number of that is 12.

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So this is very surprising.

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It means that when we look at people

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and see a person from Africa

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and a person from Europe or Asia,

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we cannot, for a single position in the genome with 100 percent accuracy,

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predict what the person would carry.

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And only for 12 positions

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can we hope to be 95 percent right.

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This may be surprising,

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because we can, of course, look at these people

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and quite easily say where they or their ancestors came from.

0:07:01.000,0:07:03.000
So what this means now

0:07:03.000,0:07:05.000
is that those traits we then look at

0:07:05.000,0:07:07.000
and so readily see --

0:07:07.000,0:07:10.000
facial features, skin color, hair structure --

0:07:10.000,0:07:14.000
are not determined by single genes with big effects,

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but are determined by many different genetic variants

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that seem to vary in frequency

0:07:19.000,0:07:21.000
between different parts of the world.

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There is another thing with those traits

0:07:24.000,0:07:27.000
that we so easily observe in each other

0:07:27.000,0:07:29.000
that I think is worthwhile to consider,

0:07:29.000,0:07:32.000
and that is that, in a very literal sense,

0:07:32.000,0:07:35.000
they're really on the surface of our bodies.

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They are what we just said --

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facial features, hair structure, skin color.

0:07:40.000,0:07:42.000
There are also a number of features

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that vary between continents like that

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that have to do with how we metabolize food that we ingest,

0:07:48.000,0:07:50.000
or that have to do

0:07:50.000,0:07:53.000
with how our immune systems deal with microbes

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that try to invade our bodies.

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But so those are all parts of our bodies

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where we very directly interact with our environment,

0:08:00.000,0:08:04.000
in a direct confrontation, if you like.

0:08:04.000,0:08:06.000
It's easy to imagine

0:08:06.000,0:08:08.000
how particularly those parts of our bodies

0:08:08.000,0:08:11.000
were quickly influenced by selection from the environment

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and shifted frequencies of genes

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that are involved in them.

0:08:15.000,0:08:18.000
But if we look on other parts of our bodies

0:08:18.000,0:08:20.000
where we don't directly interact with the environment --

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our kidneys, our livers, our hearts --

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there is no way to say,

0:08:25.000,0:08:27.000
by just looking at these organs,

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where in the world they would come from.

0:08:31.000,0:08:33.000
So there's another interesting thing

0:08:33.000,0:08:36.000
that comes from this realization

0:08:36.000,0:08:40.000
that humans have a recent common origin in Africa,

0:08:40.000,0:08:43.000
and that is that when those humans emerged

0:08:43.000,0:08:45.000
around 100,000 years ago or so,

0:08:45.000,0:08:47.000
they were not alone on the planet.

0:08:47.000,0:08:50.000
There were other forms of humans around,

0:08:50.000,0:08:53.000
most famously perhaps, Neanderthals --

0:08:53.000,0:08:55.000
these robust forms of humans,

0:08:55.000,0:08:57.000
compared to the left here

0:08:57.000,0:09:01.000
with a modern human skeleton on the right --

0:09:01.000,0:09:04.000
that existed in Western Asia and Europe

0:09:04.000,0:09:06.000
since several hundreds of thousands of years.

0:09:06.000,0:09:08.000
So an interesting question is,

0:09:08.000,0:09:10.000
what happened when we met?

0:09:10.000,0:09:12.000
What happened to the Neanderthals?

0:09:12.000,0:09:14.000
And to begin to answer such questions,

0:09:14.000,0:09:18.000
my research group -- since over 25 years now --

0:09:18.000,0:09:20.000
works on methods to extract DNA

0:09:20.000,0:09:22.000
from remains of Neanderthals

0:09:22.000,0:09:24.000
and extinct animals

0:09:24.000,0:09:27.000
that are tens of thousands of years old.

0:09:27.000,0:09:30.000
So this involves a lot of technical issues

0:09:30.000,0:09:32.000
in how you extract the DNA,

0:09:32.000,0:09:35.000
how you convert it to a form you can sequence.

0:09:35.000,0:09:37.000
You have to work very carefully

0:09:37.000,0:09:40.000
to avoid contamination of experiments

0:09:40.000,0:09:43.000
with DNA from yourself.

0:09:43.000,0:09:46.000
And this then, in conjunction with these methods

0:09:46.000,0:09:50.000
that allow very many DNA molecules to be sequenced very rapidly,

0:09:50.000,0:09:52.000
allowed us last year

0:09:52.000,0:09:55.000
to present the first version of the Neanderthal genome,

0:09:55.000,0:09:57.000
so that any one of you

0:09:57.000,0:09:59.000
can now look on the Internet, on the Neanderthal genome,

0:09:59.000,0:10:02.000
or at least on the 55 percent of it

0:10:02.000,0:10:05.000
that we've been able to reconstruct so far.

0:10:05.000,0:10:07.000
And you can begin to compare it to the genomes

0:10:07.000,0:10:10.000
of people who live today.

0:10:10.000,0:10:12.000
And one question

0:10:12.000,0:10:14.000
that you may then want to ask

0:10:14.000,0:10:16.000
is, what happened when we met?

0:10:16.000,0:10:18.000
Did we mix or not?

0:10:18.000,0:10:20.000
And the way to ask that question

0:10:20.000,0:10:23.000
is to look at the Neanderthal that comes from Southern Europe

0:10:23.000,0:10:25.000
and compare it to genomes

0:10:25.000,0:10:27.000
of people who live today.

0:10:27.000,0:10:29.000
So we then look

0:10:29.000,0:10:31.000
to do this with pairs of individuals,

0:10:31.000,0:10:33.000
starting with two Africans,

0:10:33.000,0:10:35.000
looking at the two African genomes,

0:10:35.000,0:10:38.000
finding places where they differ from each other,

0:10:38.000,0:10:41.000
and in each case ask: What is a Neanderthal like?

0:10:41.000,0:10:44.000
Does it match one African or the other African?

0:10:44.000,0:10:47.000
We would expect there to be no difference,

0:10:47.000,0:10:49.000
because Neanderthals were never in Africa.

0:10:49.000,0:10:52.000
They should be equal, have no reason to be closer

0:10:52.000,0:10:55.000
to one African than another African.

0:10:55.000,0:10:57.000
And that's indeed the case.

0:10:57.000,0:10:59.000
Statistically speaking, there is no difference

0:10:59.000,0:11:03.000
in how often the Neanderthal matches one African or the other.

0:11:03.000,0:11:05.000
But this is different

0:11:05.000,0:11:09.000
if we now look at the European individual and an African.

0:11:09.000,0:11:12.000
Then, significantly more often,

0:11:12.000,0:11:14.000
does a Neanderthal match the European

0:11:14.000,0:11:16.000
rather than the African.

0:11:16.000,0:11:19.000
The same is true if we look at a Chinese individual

0:11:19.000,0:11:21.000
versus an African,

0:11:21.000,0:11:25.000
the Neanderthal will match the Chinese individual more often.

0:11:25.000,0:11:27.000
This may also be surprising

0:11:27.000,0:11:29.000
because the Neanderthals were never in China.

0:11:29.000,0:11:33.000
So the model we've proposed to explain this

0:11:33.000,0:11:35.000
is that when modern humans came out of Africa

0:11:35.000,0:11:38.000
sometime after 100,000 years ago,

0:11:38.000,0:11:40.000
they met Neanderthals.

0:11:40.000,0:11:43.000
Presumably, they did so first in the Middle East,

0:11:43.000,0:11:45.000
where there were Neanderthals living.

0:11:45.000,0:11:47.000
If they then mixed with each other there,

0:11:47.000,0:11:49.000
then those modern humans

0:11:49.000,0:11:51.000
that became the ancestors

0:11:51.000,0:11:53.000
of everyone outside Africa

0:11:53.000,0:11:56.000
carried with them this Neanderthal component in their genome

0:11:56.000,0:11:58.000
to the rest of the world.

0:11:58.000,0:12:01.000
So that today, the people living outside Africa

0:12:01.000,0:12:04.000
have about two and a half percent of their DNA

0:12:04.000,0:12:06.000
from Neanderthals.

0:12:06.000,0:12:09.000
So having now a Neanderthal genome

0:12:09.000,0:12:11.000
on hand as a reference point

0:12:11.000,0:12:13.000
and having the technologies

0:12:13.000,0:12:15.000
to look at ancient remains

0:12:15.000,0:12:17.000
and extract the DNA,

0:12:17.000,0:12:21.000
we can begin to apply them elsewhere in the world.

0:12:21.000,0:12:24.000
And the first place we've done that is in Southern Siberia

0:12:24.000,0:12:26.000
in the Altai Mountains

0:12:26.000,0:12:28.000
at a place called Denisova,

0:12:28.000,0:12:30.000
a cave site in this mountain here,

0:12:30.000,0:12:33.000
where archeologists in 2008

0:12:33.000,0:12:35.000
found a tiny little piece of bone --

0:12:35.000,0:12:37.000
this is a copy of it --

0:12:37.000,0:12:41.000
that they realized came from the last phalanx

0:12:41.000,0:12:44.000
of a little finger of a pinky of a human.

0:12:44.000,0:12:46.000
And it was well enough preserved

0:12:46.000,0:12:49.000
so we could determine the DNA from this individual,

0:12:49.000,0:12:51.000
even to a greater extent

0:12:51.000,0:12:53.000
than for the Neanderthals actually,

0:12:53.000,0:12:55.000
and start relating it to the Neanderthal genome

0:12:55.000,0:12:58.000
and to people today.

0:12:58.000,0:13:00.000
And we found that this individual

0:13:00.000,0:13:03.000
shared a common origin for his DNA sequences

0:13:03.000,0:13:07.000
with Neanderthals around 640,000 years ago.

0:13:07.000,0:13:10.000
And further back, 800,000 years ago

0:13:10.000,0:13:12.000
is there a common origin

0:13:12.000,0:13:14.000
with present day humans.

0:13:14.000,0:13:16.000
So this individual comes from a population

0:13:16.000,0:13:19.000
that shares an origin with Neanderthals,

0:13:19.000,0:13:22.000
but far back and then have a long independent history.

0:13:22.000,0:13:24.000
We call this group of humans,

0:13:24.000,0:13:26.000
that we then described for the first time

0:13:26.000,0:13:28.000
from this tiny, tiny little piece of bone,

0:13:28.000,0:13:30.000
the Denisovans,

0:13:30.000,0:13:33.000
after this place where they were first described.

0:13:33.000,0:13:36.000
So we can then ask for Denisovans

0:13:36.000,0:13:38.000
the same things as for the Neanderthals:

0:13:38.000,0:13:42.000
Did they mix with ancestors of present day people?

0:13:42.000,0:13:44.000
If we ask that question,

0:13:44.000,0:13:46.000
and compare the Denisovan genome

0:13:46.000,0:13:48.000
to people around the world,

0:13:48.000,0:13:50.000
we surprisingly find

0:13:50.000,0:13:52.000
no evidence of Denisovan DNA

0:13:52.000,0:13:57.000
in any people living even close to Siberia today.

0:13:57.000,0:13:59.000
But we do find it in Papua New Guinea

0:13:59.000,0:14:03.000
and in other islands in Melanesia and the Pacific.

0:14:03.000,0:14:05.000
So this presumably means

0:14:05.000,0:14:08.000
that these Denisovans had been more widespread in the past,

0:14:08.000,0:14:11.000
since we don't think that the ancestors of Melanesians

0:14:11.000,0:14:13.000
were ever in Siberia.

0:14:13.000,0:14:15.000
So from studying

0:14:15.000,0:14:18.000
these genomes of extinct humans,

0:14:18.000,0:14:21.000
we're beginning to arrive at a picture of what the world looked like

0:14:21.000,0:14:24.000
when modern humans started coming out of Africa.

0:14:24.000,0:14:27.000
In the West, there were Neanderthals;

0:14:27.000,0:14:29.000
in the East, there were Denisovans --

0:14:29.000,0:14:31.000
maybe other forms of humans too

0:14:31.000,0:14:33.000
that we've not yet described.

0:14:33.000,0:14:36.000
We don't know quite where the borders between these people were,

0:14:36.000,0:14:38.000
but we know that in Southern Siberia,

0:14:38.000,0:14:40.000
there were both Neanderthals and Denisovans

0:14:40.000,0:14:43.000
at least at some time in the past.

0:14:43.000,0:14:46.000
Then modern humans emerged somewhere in Africa,

0:14:46.000,0:14:49.000
came out of Africa, presumably in the Middle East.

0:14:49.000,0:14:52.000
They meet Neanderthals, mix with them,

0:14:52.000,0:14:55.000
continue to spread over the world,

0:14:55.000,0:14:58.000
and somewhere in Southeast Asia,

0:14:58.000,0:15:00.000
they meet Denisovans and mix with them

0:15:00.000,0:15:03.000
and continue on out into the Pacific.

0:15:03.000,0:15:06.000
And then these earlier forms of humans disappear,

0:15:06.000,0:15:09.000
but they live on a little bit today

0:15:09.000,0:15:11.000
in some of us --

0:15:11.000,0:15:14.000
in that people outside of Africa have two and a half percent of their DNA

0:15:14.000,0:15:16.000
from Neanderthals,

0:15:16.000,0:15:18.000
and people in Melanesia

0:15:18.000,0:15:21.000
actually have an additional five percent approximately

0:15:21.000,0:15:24.000
from the Denisovans.

0:15:24.000,0:15:26.000
Does this then mean that there is after all

0:15:26.000,0:15:28.000
some absolute difference

0:15:28.000,0:15:31.000
between people outside Africa and inside Africa

0:15:31.000,0:15:33.000
in that people outside Africa

0:15:33.000,0:15:35.000
have this old component in their genome

0:15:35.000,0:15:37.000
from these extinct forms of humans,

0:15:37.000,0:15:39.000
whereas Africans do not?

0:15:39.000,0:15:42.000
Well I don't think that is the case.

0:15:42.000,0:15:44.000
Presumably, modern humans

0:15:44.000,0:15:46.000
emerged somewhere in Africa.

0:15:46.000,0:15:49.000
They spread across Africa also, of course,

0:15:49.000,0:15:52.000
and there were older, earlier forms of humans there.

0:15:52.000,0:15:54.000
And since we mixed elsewhere,

0:15:54.000,0:15:56.000
I'm pretty sure that one day,

0:15:56.000,0:15:58.000
when we will perhaps have a genome

0:15:58.000,0:16:00.000
of also these earlier forms in Africa,

0:16:00.000,0:16:02.000
we will find that they have also mixed

0:16:02.000,0:16:05.000
with early modern humans in Africa.

0:16:06.000,0:16:08.000
So to sum up,

0:16:08.000,0:16:10.000
what have we learned from studying genomes

0:16:10.000,0:16:12.000
of present day humans

0:16:12.000,0:16:14.000
and extinct humans?

0:16:14.000,0:16:16.000
We learn perhaps many things,

0:16:16.000,0:16:21.000
but one thing that I find sort of important to mention

0:16:21.000,0:16:24.000
is that I think the lesson is that we have always mixed.

0:16:24.000,0:16:26.000
We mixed with these earlier forms of humans,

0:16:26.000,0:16:28.000
wherever we met them,

0:16:28.000,0:16:32.000
and we mixed with each other ever since.

0:16:32.000,0:16:34.000
Thank you for your attention.

0:16:34.000,0:16:40.000
(Applause)